Anti-diabetic chemical drugs
Anti-diabetic chemical drugs are classified by mechanism of action: 1) insulin and its analogues; 2) sulfonylureas (gliphenylurea (euglycemia), glipizide (DAMAC), glipizide (Rexin), glipizide (Glucophage), glimepiride (Amoxicillin)); 3) biguanides; 4) alpha-glucosidase inhibitors (bactrim (acarbose); carboplatin (acarbose); bexin (voglibose,)); 5) thiazolidinedione derivatives (pioglitazone (etin tablets, rosiglitazone maleate); oxybutynin (miglitol,)); and 6) thiazolidinedione derivatives (pioglitazone (etin tablets, rosiglitazone maleate). (Voglibose); Ottenapple (Miglitol,)). 5, thiazolidinedione derivatives (pioglitazone (Ettin tablets), rosiglitazone maleate (Vindia)). 6, pro-insulin secretagogues (Repaglinide (Novalaxone, Pregabalin), (2) nateglinide (Tangli, Tangri), (3) Miglitazone). 7, seven major categories of Chinese patent medicines.
1, thiazolidinediones (insulin sensitizers)
Thiazolidinediones (TZDs) is a new class of drugs for the treatment of type II diabetes. These drugs are activated by binding to receptors in the body, thus improving insulin resistance, hyperinsulinemia and hyperglycemia metabolic disorders in type II diabetic patients. At the same time, this class of drugs also shows effects in lowering blood pressure, regulating lipid metabolism, inhibiting inflammatory response, anti-atherosclerosis and protection of the kidney.
The first successfully developed thiazolidinediones were cycloglitazone, engramciton and troglitazone. These drugs were gradually phased out or withdrawn from the market due to their lower potency, serious adverse effects and hepatotoxicity. The insulin sensitizers currently in clinical use are pioglitazone from Takeda, Japan, and rosiglitazone maleate from GlaxoSmithKline.
Thiazolidinediones are characterized by their ability to significantly enhance the body’s tissue sensitivity to insulin, improve pancreatic β-cell function, and achieve long-term control of blood glucose, thereby reducing the risk of diabetic complications. Because of their good tolerability and safety, they have the potential to slow down the progression of diabetes. Under the influence of this great application prospect, the research and development of thiazolidinedione series of drugs abroad is far from stopping, and the drugs waiting to be marketed include Farglitazar developed by GlaxoSmithKline, UK, and Darglitazoan developed by Takeda Pharmaceuticals, Japan.
Thiazolidinediones are a large and steadily growing category, accounting for 3.53% of the antidiabetic drug market in 2003, 4.08% in 2004, and 4.52% in 2005.
Domestic rosiglitazone is very aggressive against the original drug
In 2000, GlaxoSmithKline (Tianjin) has introduced rosiglitazone into the market in China, under the trade name of “Avandia” and “Anjian”. In 2000, GlaxoSmithKline (Tianjin) introduced rosiglitazone to China under the trade name “Vindia”.
After the global launch of rosiglitazone, the sales increased steadily, and subsequently, rosiglitazone/metformin combination (Avandamet) and rosiglitazone/glimepiride combination (Avandaryl) were developed in the market one after another.
In 2006, GlaxoSmithKline’s rosiglitazone/metformin combination was approved by SFDA to be marketed in China under the trade name of Avandamet. In 2005, the sales of rosiglitazone and its compound formulations reached US$2.4 billion, making it the top anti-diabetic drug, and in 2006, it increased by 27% year-on-year and exceeded US$3 billion.
In 2005, Guizhou Shengjitang Pharmaceutical Co., Ltd.’s tablet “Shengmin” and Jiangsu Huanghe Pharmaceutical Co.’s capsule “Orova” were also approved for production and marketing, forming a market pattern of 1:6 between the original and domestic drugs.
Domestic Pioglitazone dominates the domestic market
Pioglitazone was developed by Takeda/Lilly in Japan and was marketed in the United States on July 15, 1999 after receiving FDA approval under the trade name “Actos”. In 2005, Takeda’s original drug was registered in China and marketed under the trade name “Aceto”.
There are 12 manufacturers of pioglitazone for domestic sample hospitals, among which the top 5 are Beijing Taiyang Pharmaceutical’s “Etin”, Jiangsu Hengrui Pharmaceutical’s “Ruitong”, Hangzhou Zhongmei Huadong Pharmaceutical’s “Caspian “, Tianjin Wu Tian Pharmaceuticals “Aceto”, Sichuan Baoguang Pharmaceuticals “Betanin” occupies 98, 27% of the share, while Zhejiang Kang’anbei Pharmaceuticals, Shanghai Kaibao Pharmaceuticals, Shandong Zibo Xinda Pharmaceuticals and other seven products Only 1, 73%, although still in the initial stage, but also shows rapid growth.
At present, the thiazolidinediones commonly used in clinical practice are mainly rosiglitazone and pioglitazone two categories. Clinically, they are used as insulin sensitizers to increase the body’s sensitivity to insulin and reduce insulin resistance.
The rosiglitazone class includes: Vindia (rosiglitazone maleate), 2 mg and 4 mg per tablet (GlaxoSmithKline); Tairo (rosiglitazone sodium), 4 mg per tablet (Taiji Pharmaceutical); Aynergy (rosiglitazone), 4 mg per tablet (Chengdu Hengrui); Vigorol (rosiglitazone hydrochloride), 4 mg per tablet (Shanghai 3D).
The pioglitazone class includes: Ettin (pioglitazone hydrochloride), 15 mg per tablet (Taiyang Pharmaceutical); Caspian (pioglitazone hydrochloride), 15 mg per tablet (Zhongmei Huadong); Ritong (pioglitazone hydrochloride), 15 mg per tablet (Chengdu Hengrui).
All of the above drugs are medically insured drugs.
Thiazolidinediones can directly reduce insulin resistance, significantly improve beta-cell function, achieve long-term control of blood glucose, thereby reducing the risk of diabetic complications, and at the same time have good tolerability and safety, and therefore have the potential to delay the progression of diabetes and great application prospects.
The onset of action of thiazolidinediones is slower than that of other hypoglycemic drugs. They take time to take effect and do not achieve optimal efficacy in a short period of time. It usually takes several weeks or even months to achieve the maximum effect. Therefore, when using thiazolidinediones, it is also necessary to achieve an adequate course of treatment. Only with adequate doses and a sufficient course of treatment can beta-cell function be better protected, cardiovascular risk factors be reduced, and disease progression be delayed.
Thiazolidinediones have the effect of reducing cardiovascular risk factors and delaying disease progression because they reduce insulin resistance, improve and protect β-cell function, and improve glucose and lipid metabolism. Therefore, in clinical practice, thiazolidinediones should be given to obese or overweight type 2 diabetic patients, as well as non-obese type 2 diabetic patients with metabolic syndrome, as a priority and as early as possible. The early use of thiazolidinediones does not only mean the reduction and achievement of blood glucose, glycosylated hemoglobin and lipid levels, but also the protection and improvement of β-cell function, which can slow down the progression of diabetes, improve many cardiovascular risk factors, prevent the occurrence and development of chronic complications and cardiovascular events, improve the quality of life of patients, and reduce the rate of disability and The following is a list of the most important factors that can be considered in the treatment of diabetes mellitus
Who is suitable for thiazolidinediones?
(1) Patients with type 2 diabetes mellitus.
(2) Patients with type 2 diabetes mellitus who are poorly controlled by diet and exercise.
(3) Patients with type 2 diabetes mellitus who are poorly controlled with metformin or sulfonylureas alone.
(4) Patients with type 2 diabetes mellitus poorly controlled by insulin alone.
What are the side effects of thiazolidinediones? What are the precautions in their use?
The main side effects of thiazolidinediones are: abnormal liver function, edema, weight gain, and mild to moderate anemia. The incidence of anemia is higher when combined with metformin than with metformin alone or with sulfonylureas.
The following should be noted when taking thiazolidinediones.
(1) The mechanism of action of thiazolidinediones determines that they can only work in the presence of insulin, so they should not be used in patients with type 1 diabetes or diabetic ketoacidosis.
(2) The use of thiazolidinediones must be routinely tested for liver function before use, and should not be used in patients with liver disease or hepatic impairment.
(3) All people taking thiazolidinediones must be regularly monitored liver function, the initial year every 2 months to recheck liver function, and then regularly.
(4) thiazolidinediones in combination with other oral hypoglycemic drugs or insulin, there is a possibility of hypoglycemia, the dose of the combined drugs can be adjusted according to the actual blood sugar situation of the patient. When this drug is combined with insulin, the dosage of insulin can be reduced.
(5) Patients with renal impairment do not need to adjust the dose of this drug alone; because metformin is prohibited in patients with renal impairment, this product should not be combined with metformin in such patients.
(6) No age-related dose adjustment is necessary in elderly patients.
(7) In patients with combined polycystic ovary syndrome, there is a potential for conception after treatment with this drug.
(8) Use with caution in patients with grade 1 or 2 heart failure.
What are the contraindications of thiazolidinediones?
(1) Contraindicated in patients with known hypersensitivity to this product or its components.
(2) Contraindicated in patients with diabetic ketoacidosis.
(3) Not suitable for use in patients with type l diabetes.
(4) This drug should be used with caution in patients with edema.
(5) Not suitable for patients with grade 3 or 4 cardiac dysfunction. Thiazolidinediones can cause fluid retention and may aggravate the risk of congestive heart failure.
(6) Contraindicated in patients with active liver disease or serum alanine aminotransferase 2,5 to 3 times above the upper limit of normal.
(7) This product is not recommended for patients under 18 years of age.
(8) Pregnant and nursing women should avoid taking it.
Can thiazolidinediones be used in combination with other hypoglycemic agents?
Thiazolidinediones can be used in combination with other oral hypoglycemic agents or insulins with complementary mechanisms of action to achieve better glucose lowering effects. Thiazolidinediones can be combined with sulfonylureas, glinides, biguanides, alpha-glucosidase inhibitors and various types of insulins, but the dose of the combined drugs should be adjusted according to the actual blood glucose situation of the patient. When combined with insulin, the dosage of insulin can be gradually reduced.
2.α-glucosidase inhibitor
What are α-glucosidase inhibitors?
Alpha-glucosidase inhibitors are a class of oral hypoglycemic drugs that can be used to treat diabetes by delaying the absorption of carbohydrates from the intestinal tract. alpha-glucosidase inhibitors are relatively mature drugs for the treatment of diabetes and have been widely used in clinical practice. The mechanism of action is: competitive inhibition of various α-glucosidases located in the small intestine slows down the breakdown of starch into glucose, thereby slowing down the absorption of glucose in the intestine and reducing postprandial hyperglycemia. α-glucosidase inhibitors do not stimulate insulin secretion by β-cells, but can reduce postprandial insulin levels, indicating that they can increase insulin sensitivity.
What are the commonly used α-glucosidase inhibitors?
The main α-glucosidase inhibitors that have entered the market and are commonly used in clinical practice are: Bactrim (acarbose), 50 mg per tablet (Bayer, Germany); Carboplatin (acarbose), 50 mg per tablet (Zhongmei Huadong); Bexin (voglibose), 0,2 mg per tablet (Tianjin Wutian); Ottenapple (miglitol), 50 mg per tablet ( Sichuan Vio). Among the above drugs, Bactrim and Carboplatin are medically insured drugs, while Bexin and Aotipine have not yet entered the medical insurance catalog.
What are the characteristics of α-glucosidase inhibitors?
(1) Inhibit α-glucosidase on the surface of small intestinal epithelial cells.
(2) Delay the absorption of carbohydrates.
(3) Does not inhibit the absorption of protein and fat.
(4) Generally does not cause impaired absorption of nutrients.
(5) The binding time of drug and enzyme is about 4-6 hours, after which the activity of enzyme can be restored again.
(6) There are almost no side effects and accumulation effects on liver and kidney.
(7) It mainly reduces postprandial blood glucose.
What are the benefits of using α-glucosidase inhibitors?
The following benefits are associated with the administration of alpha-glucosidase.
It significantly reduces the risk of developing type 2 diabetes in people with impaired glucose tolerance. The glucose toxicity of postprandial hyperglycemia can aggravate insulin resistance and defective insulin secretion, and when only about 50% of pancreatic β-cell function is left, fasting glucose rises and type 2 diabetes develops in people with impaired glucose tolerance. Therefore, controlling postprandial hyperglycemia is an important means to stop the development of type 2 diabetes in people with impaired glucose tolerance.
It can significantly reduce the risk of macroangiopathy in diabetic patients. Postprandial hyperglycemia can cause vasoconstriction and increased permeability of blood vessels and increased adhesion of vascular endothelial cells, resulting in vascular damage, which is the basis for the development of macrovascular lesions such as atherosclerosis caused by diabetes. Therefore, controlling postprandial hyperglycemia can significantly reduce the risk of macrovascular lesions in patients.
It can significantly reduce the risk of cardiovascular complications and death in patients. Numerous epidemiological studies and clinical trials have confirmed that postprandial hyperglycemia is a high-risk factor for cardiovascular complications and death.
It also reduces postprandial insulin levels and may increase insulin sensitivity.
Who is indicated for alpha-glucosidase inhibitors?
(1) Patients with type 2 diabetes.
(2) Patients with type 2 diabetes mellitus who are not well controlled by diet and exercise therapy.
(3) Patients with type 2 diabetes mellitus who are not well controlled with metformin or sulfonylureas alone.
(4) Patients with type 2 diabetes poorly controlled with insulin alone.
(5) Patients with type 1 diabetes who can be treated with insulin, which can reduce insulin dosage and stabilize blood sugar.
What are the side effects?
Gastrointestinal reactions: abdominal distension, abdominal pain, diarrhea, gastrointestinal cramping pain, persistent constipation, etc. Others include bowel sounds, nausea, vomiting, and loss of appetite. It can be relieved by long-term application or dose reduction.
Weakness, headache, vertigo, skin itching or rash are less common.
Hypoglycemia may occur in combination with other hypoglycemic agents, such as insulin, sulfonylurea or metformin.
What are the precautions in use?
(1) It should not be used as the main treatment for patients with type 1 diabetes.
(2) Before using α-glucosidase inhibitors, liver and kidney function should be tested routinely.
(3) The occurrence of hypoglycemia should be observed when other hypoglycemic drugs are used in combination. The dose of the combined drug can be adjusted according to the patient’s blood sugar condition. When this drug is used in combination with insulin, the dosage of insulin can be reduced.
(4) When α-glucosidase inhibitor is combined with other oral hypoglycemic drugs or insulin, if hypoglycemia occurs, it should be treated with sedation or oral glucose. Taking sucrose or general sweet food is not effective.
(5) It should be taken together with the first meal.
What are the contraindications?
(1) This product is contraindicated in cases of intestinal inflammation, chronic intestinal diseases with malabsorption or digestive problems, partial intestinal obstruction or tendency to intestinal obstruction, colonic ulcers, and hernia, which may be aggravated by intestinal insufflation.
(2) Not used in patients with abnormal liver function.
(3) Not to be used in patients with renal impairment and blood creatinine exceeding 176.8 micromol/liter.
(4) Not recommended for those with severe hematopoietic system dysfunction.
(5) Not recommended for those with fever and infection.
(6) Not recommended for pregnant and lactating women.
(7) Not recommended for children under 18 years of age.
(8) Not recommended for people with malignant tumors.
(9) Not recommended for those who are overly addicted to alcohol and tobacco.
(10) Not recommended for those who are using laxatives or antidiarrheal drugs.
(11) This product is not recommended when taking enzyme preparations such as amylase and pancreatic enzymes that help digestion.
Can it be used in combination with other hypoglycemic drugs?
Alpha-glucosidase inhibitors can be used in combination with other oral hypoglycemic agents or insulin to achieve better glucose-lowering effect through complementary mechanisms. alpha-glucosidase inhibitors can be combined with sulfonylureas, glinides, biguanides, thiazolidinediones and various types of insulins, but the dose of the combined drugs should be adjusted according to the patient’s blood glucose condition. When combined with insulin, the dosage of insulin can be gradually reduced.
Special reminder: the five major types of oral hypoglycemic drugs (metformin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitors and glinides) are all prescription drugs and should be taken by diabetic patients under the guidance of a clinician’s prescription, not by themselves.
3.Nonsulfonylurea insulinotropic agents (NSUR)
Glinides are non-sulfonylurea insulin secretagogues, which are oral hypoglycemic drugs marketed in China after 2000. Mechanism of action: Binding to pancreatic β-cell specific receptors to improve the sensitivity of ATP on the pancreatic islet cell membrane. Potassium channels are closed and potassium-dependent calcium channels are inhibited from opening, allowing extracellular calcium to enter the cells and promoting stored insulin secretion without affecting intracellular insulin biosynthesis. These drugs can stimulate insulin secretion and reduce glycated hemoglobin (Hb Alc) and postprandial blood glucose (PBG) in type II diabetic patients. Combined with metformin and thiazolidinediones, they can reduce β-cell load and delay the survival of pancreatic islet cells, with significant efficacy in people with isolated postprandial hyperglycemia (IPH), people with first-phase disorders of insulin secretion and people with irregular diet.
2.Indications
(1) Type II diabetic patients whose hyperglycemia cannot be effectively controlled by diet control and exercise.
(2) Repaglinide tablets can be combined with metformin, and the combination of the two has a synergistic effect on blood glucose control.
(3) Patients with type II diabetes mellitus with mild to moderate hepatic and renal impairment, elderly patients with diabetes mellitus.
(4) Combination therapy for patients with blood glucose level FPG>9mmol/L (>160mg/dl).
(5) Patients with newly diagnosed hyperglycemic FPG>9mmol/L (>160mg/dl) who have not taken other hypoglycemic drugs.
(6) Patients who cannot tolerate metformin.
3.Drug introduction
(1) Repaglinide Repaglinide (Novaluron, Pregabalin)
Features: It is a benzoic acid derivative, with the characteristics of fast absorption and fast onset of action. The mechanism of stimulating insulin secretion is similar to that of sulfonylurea, which can significantly increase the plasma insulin level and reduce the level of glycated hemoglobin. By closing the ATP-dependent potassium channel, the drug can promote the release of the synthesized insulin in the pancreatic islet cells and restore the normal post-prandial insulin secretion pattern. It starts to take effect 30 minutes after oral administration, reaches its peak within 1 hour, and is cleared within 4-6 hours. The half-life of plasma is about 1 hour, and it is fast in and fast out. It effectively mimics physiological insulin secretion, which can lower fasting blood glucose (FBG) and postprandial blood glucose, without the need to take it half an hour before meal. Its metabolites are mainly excreted from bile, and a small portion (less than 8%) is excreted from urine. The original form of the drug in the feces is less than 1%.
Specification: 0,5mg/tablet
Dosage: 0,5-4mg, maximum dose 16mg/day. The dose should be adjusted carefully and may be adjusted weekly or biweekly if needed.
Dosage: The dosing time can be taken within 0-30 minutes before meals, because the pro-insulin secretion response occurs within 30 minutes of oral ingestion of Repaglinide tablets. The drug is usually taken within 15 minutes before meals.
Side effects: ① Hypoglycemia: These reactions are usually mild and can be easily corrected by giving carbohydrates.
② Visual abnormalities: Changes in blood glucose levels are known to cause temporary visual abnormalities, especially at the start of treatment. Only a very small number of cases have reported these visual abnormalities at the start of treatment with Repaglinide tablets, but there have been no cases of discontinuation of Repaglinide tablets in clinical trials as a result.
(iii) Gastrointestinal: Gastrointestinal reactions such as abdominal pain, diarrhea, nausea, vomiting and constipation have been reported in clinical trials. There was no difference in the frequency and severity of these symptoms compared to other oral hypoglycemic drugs.
④Hepatic enzyme system: Individual cases reported elevated liver enzyme indices during treatment with Repaglinide tablets. Most cases were mild and transient, and very few patients discontinued treatment due to elevated enzyme indices.
⑤ Allergic reactions: Allergic skin reactions, such as pruritus, erythema, and urticaria, may occur.
Precautions: ① Although Repaglinide is mainly excreted by bile, it is still used with caution in patients with renal insufficiency.
②Dosing without meals may cause hypoglycemia, and combining with metformin will increase the risk of hypoglycemia.
③Used with caution in patients with hepatic insufficiency.
④Significant hyperglycemia may occur in the event of stress reactions, such as fever, trauma, infection or surgery.
⑤ Repaglinide tablets have not been studied in patients over 75 years of age. Therefore, they should not be used in patients over 75 years of age.
(2) Nateglinide Nateglinide (Tangli, Tangri)
Features: It is a phenylalanine derivative, which can effectively increase the first-phase insulin secretion, thus reducing the peak of meal glucose, but does not lead to the secretion of second-phase insulin. Therefore, the chance of hypoglycemia is low, and it has the effect of protecting pancreatic β-cells. The blood glucose-dependent insulin stimulating effect reduces insulin secretion at low blood glucose levels. It has a “fast on/fast off” effect on β-cells, with rapid onset of action and rapid disappearance. The onset of action is 15 minutes, the maximum blood concentration is 1-2 hours, and the duration is 4-6 hours. Combined with metformin or glitazones, the blood sugar control is better.
Specification: 60mg, 120mg, 180mg tablets
Dosage: 30-240 mg/day, the maximum dose should not exceed 360 mg/day. Adjusted according to regular Hb Alc test results, Hb Alc 65 years, severe hypertension, significant retinopathy, patients who eat too little.
[Adverse effects]
Adverse reactions to biguanide hypoglycemic agents are gastrointestinal reactions, which manifest as loss of appetite, diarrhea, metallic taste in the mouth or fatigue, and weight loss. If the intestinal reactions are severe, it can be taken before or after meals instead.
[Caution]
1. Start with a small dose, adjust the dose according to blood sugar, and combine with sulfonylurea hypoglycemic agents if necessary.
2. Take with or after meals to reduce gastrointestinal reactions.
3.Regularly check liver and kidney function and the presence of anemia.
4. Combined use with sulfonylureas can enhance the hypoglycemic effect.
5.If contraindication situation occurs, the drug should be stopped immediately.
6.The use of biguanide alone usually does not cause hypoglycemic reactions, but can occur when combined with sulfonylurea or insulin.
[Rational use]
Dosing time: In order to reduce the gastrointestinal side effects of biguanides, it is generally recommended to take them after meals.
[Toxic side effects]
The main side effects of biguanide hypoglycemic drugs include.
(1) lactic acidosis: The most serious side effect of biguanide hypoglycemic drugs, especially hypoglycemic ling, is lactic acidosis. When the dose of hypoglycemia is greater than 150 mg per day, it will increase the amount of lactic right ascending in the body. Older people, or diabetic patients with cardiovascular, lung, liver and kidney problems although they are not too old, are prone to lactic acidosis due to lack of oxygen in the body and increased production of lactic acid, while its metabolism and removal are impaired, and the risk of lactic acidosis increases significantly in such patients who take a larger amount of glucagon.
(2) Gastrointestinal reactions: manifested as decreased appetite, nausea, vomiting, dry mouth, bitter mouth, abdominal distension, diarrhea, etc. The possibility of gastrointestinal symptoms caused by glucagon is greater than that of metformin, and its degree is also more serious than that of metformin.
(3) liver and kidney damage: for liver function is not normal. (3) liver and kidney damage: for diabetic patients with elevated transaminases, or for patients with poor kidney function, persistent positive urine protein, or even the accumulation and elevation of creatinine and urea nitrogen and other wastes in the blood, biguanide hypoglycemic drugs have the risk of further deterioration of liver and kidney function, it is best not to use.
(4) aggravate ketoacidosis: hypoglycemic can promote the production of ketone bodies, so diabetic patients with ketoacidosis or ketoacidosis tendency should not use it.